There is no robust evidence to support the use of ivermectin in children under 15 kg of weight. There is no evidence to support the use of ivermectin during pregnancy.
Guzzo et al. Smit et al. The in vitro experiments by Caly et al. COVID is a public health emergency of international concern and there is no specific treatment for it. This fact, together with the excellent safety profile of ivermectin combine to warrant research on its potential use.
Additionally, extrapolating directly from a Petri dish into a live organism is not correct. Several factors may contribute to make ivermectin efficacious in vivo at lower doses than those described by Caly et al, here are some of them:.
In summary, there is equipoise. This is a term used in bioethics to define a situation in which there is reasonable doubt of whether a drug might be of use or not. The process for bringing a drug into widespread use is highly regulated. This is for good reasons. Lessons have been learned after some serious tragedies. The main requisites for approving a drug to be used at population level is proven efficacy and safety. For ivermectin, there is robust evidence of safety when used for the approved indication at the approved doses.
There is very limited evidence about the safety of ivermectin at higher doses see table link above and even less evidence for its safety when used in COVID patients that tend to have proinflammatory states. These pro-inflammatory states may increase the penetration of ivermectin into the central nervous system with unknown consequences see safety above.
Other potential issues include drug-drug interactions with some antivirals given to COVID patients such as ritonavir which may increase the levels of ivermectin. Given the absence of reasonable evidence that ivermectin has any efficacy against SARS-CoV-2, the risk-benefit analysis dictates that we should be prudent.
Given the absence of reasonable evidence that ivermectin has any efficacy against SARS-CoV-2, the risk-benefit analysis dictates that we should be prudent , i. The evidence of efficacy should come from randomized, controlled preferably double-blind clinical trials which are studies in which patients are randomly allocated to receive ivermectin or a placebo, neither the patient nor the physician knows what product they received.
Widespread use of ivermectin can and already has! Ivermectin is widely available as a veterinary drug. If there is a perception that ivermectin is beneficial for COVID patients, it is foreseeable that the veterinary formulations will be used at scale and this unsupervised use may lead to overdosing and other harmful practices.
In Peru, more than 5, indigenous were injected with veterinary ivermectin by a group with good intentions, were they conscious that they were being injected with a product intended for animal use?
Along these lines, there are also reports of injection with ivermectin-related veterinary products such as doramectin, a molecule never before used in humans with an unknown safety profile.
If indeed adverse events result from this indiscriminate use, the distribution of the drug for proven indications e. Intestinal parasites are widely prevalent in the tropics. We know that intestinal helminths modulate the way our immune system reacts to inflammation and infection. Given that ivermectin is a very good dewormer, we do not know how mass deworming may affect the way the body responds against SARS-CoV Primum non nocere or perhaps primum ivermectinum, secundum non nocere?
Moral hazard. Those receiving ivermectin as treatment or prophylaxis may feel protected and comply less efficiently with proven measures such as face masks and social distancing. Finally, we have the utmost steem for frontline health workers and do not judge the decisions and desperation of those facing dying or worsening patients. But could the use of ivermectin which is relatively safe be a way to offer something and reduce political and public pressure on policy makers and health authorities?
Many countries, faced with an exponential increase in the number of cases and deaths, were actively screening the horyzon for emerging preventive measures and treatments. The Caly et al. Contrary to many places in the world, ivermectin is locally produced in the form of a drops formulation in many countries in latinamerica.
This local availability may have played a role in its popularity. They are mostly case-control studies and even studies that compare two completely different drug schemes which can hardly prove the benefit of ivermectin. Sometimes even ecological data is used to support claims of efficacy or lack of efficacy of ivermectin against COVID, but these whole-country datasets can be twisted in ways that reflect better the views of the analyst.
Hierarchy of evidence for questions about the effectiveness of an intervention or treatment. Understanding randomised controlled trials. Archives of Disease in Childhood ; According to ClinicalTrials.
None of the trials marked as completed have results available in that platform. There are several business models in the pharmaceutical industry. Selling low volumes at high prices is an option for profit. But in the case of COVID, the target market is humanity , or about seven billion people that are susceptible to taking this drug now and in the near future. Some people who have a weak immune system need to take this medicine on a regular basis. Follow your doctor's instructions.
Since ivermectin is usually given in a single dose, you may not be on a dosing schedule. If you are on a schedule, take the missed dose as soon as you remember.
Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose. Get emergency medical help if you have signs of an allergic reaction : hives; difficult breathing; swelling of your face, lips, tongue, or throat.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. Other drugs may interact with ivermectin, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.
Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.
Every effort has been made to ensure that the information provided by Cerner Multum, Inc. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise.
Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects.
If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist. This information does not replace the advice of a doctor. The programme covered 1. For over a decade, OCP operations were exclusively based on the spraying of insecticides by helicopters and aircraft over the breeding sites of vector blackflies in order to kill their larvae. The resultant drug donation programme was the first, largest, longest running and most successful of all—and proved a model for all others that have followed.
Ivermectin began to be distributed in , with operations being organized through the independent Mectizan Donation Program MDP established and funded by Merck.
Thereafter, OCP control operations changed from exclusive vector control to larviciding combined with ivermectin treatment or, in some areas, to ivermectin treatment alone.
Ivermectin swiftly became the drug of choice for the treatment of Onchocerciasis due to its unique and potent microfilaricidal effects, the absence of severe side effects and its excellent safety. It is now the sole tool being used in disease elimination campaigns in the 16 other African countries where the disease exists, orchestrated by the African Programme for Onchocerciasis Control APOC , which commenced operations in OCP was closed in December after virtually stopping disease transmission in all target nations except Sierra Leone where operations were hampered by civil war.
Success was achieved through groundbreaking and innovative partnerships. The journey was a complex undertaking, incorporating scientific uncertainty, conflicting views, ambiguity, frustration, individual innovation and unexpected twists and turns. In the mids, the global community mobilized itself to address the major problems of neglected tropical diseases.
At the time, there were no safe and acceptable drugs available to treat Onchocerciasis, which had plagued Africa for centuries, effectively leading to the creation of the OCP and its vector control focus. Worse still, Onchocerca species would not develop to maturity in any rodents, making it impossible to screen compounds in an animal model against the target organism.
Meanwhile, with respect to research needs, TDR had identified six specific areas that required special attention, with the discovery of effective and safe chemotherapeutic agents considered to be the highest priority.
In , only two drugs were available for the treatment of onchocerciasis: diethylcarbamazine DEC and suramin. The use of both was highly unsatisfactory. DEC, which was known to kill microfilariae, caused violent and even dangerous hypersensitivity reactions in the human host. Suramin, developed 50 years previously for treatment of Sleeping Sickness, was the only drug considered for killing adult worms but was highly toxic, often causing severe and occasionally fatal reactions.
Moreover, parasitological cure of patients using DEC and suramin required lengthy and expensive treatment given under medical supervision. Therefore, the TDR Scientific Working Group SWG , composed of leading independent scientists in the field from around the globe, including industry, decided that the priority was a new and non-toxic macrofilaricide to kill adult worms , a macrofilaricide being determined to be substantially preferable to a microfilaricide which would target immature worms.
Nor was there any validated model for screening. The Committee agreed that the high cost of maintaining screening facilities for drugs against tropical diseases was a significant deterrent to industrial involvement. Unfortunately, O. Fortunately, the closest relative to the human parasite is O. The O. From on, TDR provided technical and financial support to establish a comprehensive screening system for Onchocercal filaricides.
Additionally, TDR established a unique tertiary screen, using cattle, for compounds showing positive results in any secondary screen. Some 10, compounds, many supplied by leading pharmaceutical companies as coded samples, passed through the screening network, including several from Merck.
The active compounds were identified by the international multidisciplinary collaborative team as the avermectins, with the subsequently-refined ivermectin derivative being designated the optimal compound for development. Merck scientists, under the direction of Dr William Campbell, found that the drug was active against a wide range of parasites of livestock and companion animals.
Blair, resulted in the discovery that the drug was effective against skin-dwelling microfilariae of Onchocerca cervicalis in horses. These did not actually cause clinical disease and so the finding was of little commercial significance. However, O. In July , he sent ivermectin as a coded sample , together with the results of the horse trial, to the TDR-supported tertiary cattle screen in Australia. TDR reactions to the initial data about ivermectin were rather muted, especially as it was searching for a macrofilaricide and ivermectin appeared to have little impact on adult worms.
Fortunately for all, in January , Merck decided to proceed independently to Phase I safety trials. Clinical trials of ivermectin began in , with a Phase I trial in 32 patients in Senegal followed by another trial in Paris among 20 West African immigrants. These trials were independently organized and funded by Merck, with a staff member, Dr Mohamed Aziz, previously of WHO, being the caring and committed driving force behind them. Dr Aziz started the study in Senegal with safety uppermost in his mind.
It also established that the effect lasted for at least 6 months, with no serious adverse events being observed. When Merck officials visited TDR and OCP in to present the results from the Phase I trials, each side recognised the immense potential and collaboration in earnest began. Evidence suggests that collaboration between these major partners commenced in a complex environment of mutual wariness, suspicion and shared hope that ivermectin would indeed prove to be an effective treatment for Onchocerciasis.
The situation was compounded by the fact that Merck saw ivermectin as a potentially commercial product to be used for individual patient treatment, and moved forward constantly seeking an income return on its investment. In contrast, TDR, together with OCP, saw the drug as a new community-level tool that could possibly interrupt parasite transmission and thereby help reduce the prevalence of the disease in endemic communities.
TDR and OCP consequently regarded community-based trials under field conditions as an essential step towards mass-treatment programmes, as opposed to the individual treatment in hospitals favoured by the commercial partner. With respect to official registration of ivermectin for human use, Merck, focussing on the single-patient approach, pressed ahead on its own and submitted an application to the French health authorities in based solely on the studies of the first 1, onchocerciasis patients, expecting to receive approval later that year, which it subsequently did.
Prior to registration, the involvement of TDR and OCP increased substantially, as they organised field trials, including extremely expensive, large-scale trials of the effectiveness of ivermectin in community treatment programmes, and campaigned tirelessly to get the cost of treatment reduced to an acceptable level. During the trials to test the efficacy of the drug in field settings Phase II trials starting in , Merck continued to fund much of the work, with additional financial support from OCP and TDR.
TDR was also able to influence the design of study protocols, and support applied research on onchocerciasis treatment at one of its specialized centres, the Onchocerciasis Chemotherapy Research Centre OCRC in Tamale, Ghana, where Dr Kwable Awadzi had devised a method to quantify clinical reactions to microfilaricides using a scoring system of commonly observed reactions.
Thirteen community-level Phase IV trials were conducted between —, with over , individual doses of ivermectin administered. Ivermectin proved to be virtually purpose-built to combat Onchocerciasis, which has two main manifestations, dermal damage resulting from microfilariae in the skin and ocular damage arising from microfilariae in the eye.
Until the advent of ivermectin, despite its drawbacks, DEC was the drug of choice traditionally used to treat patients with onchocercal infection. DEC acts quickly to eliminate microfilariae from the anterior chamber of the eye and keeps the eye clear for a year or more. However, the rapidity of clearance often causes ocular damage as a result of an exaggerated inflammatory reaction. Conversely, ivermectin proved to slightly increase microfilariae in the eye upon treatment, followed by a gradual reduction, reaching to near zero, similar to DEC, within six months Fig.
Most significantly, little or no resultant ocular damage occurs. Similarly, evaluation of the impact of DEC and ivermectin on dermal microfilariae, confirmed that both caused almost complete clearance within two days after treatment, reducing the load to virtually zero within eight days.
However, although both drugs produce long-term suppression of the reappearance of microfilariae, ivermectin is superior, virtually eliminating all microfilariae and maintaining that status for some 90 days, whereas the effect of DEC wanes after little more than a week Fig. Thus, ivermectin is also an ideal treatment for dermal involvement.
Lymphatic Filariasis, also known as Elephantiasis, is another devastating, highly debilitating disease that threatens over 1 billion people in more than 80 countries. Over million people are infected, 40 million of whom are seriously incapacitated and disfigured. The disease results from infection with filarial worms, Wuchereria bancrofti , Brugia malayi or B.
The parasites are transmitted to humans through the bite of an infected mosquito and develop into adult worms in the lymphatic vessels, causing severe damage and swelling lymphoedema Fig. Adult worms are responsible for the major disease manifestations, the most outwardly visible forms being painful, disfiguring swelling of the legs and genital organs Fig.
The psychological and social stigma associated with the disease are immense, as are the economic and productivity losses it causes. Ghana: an old man co-infected with onchocerciasis and lymphatic filariasis. He is partially sighted, with a worm nodule on his right leg and leopard skin on his left leg.
He also displays elephantiasis of the left leg and has a large hydrocele. With respect to the use of ivermectin for Lymphatic filariasis, again Merck took the initial lead, with TDR being involved in organising, expanding and broadening the research and clinical trials. In the mids, well before ivermectin was approved for human use to treat onchocerciasis, Merck were also undertaking trials of ivermectin to measure its impact against lymphatic filariasis and to find optimal treatment dosages.
The results showed that single-dose ivermectin and single-dose DEC worked as well as each other.
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